Reduced plasma membrane expression of dysferlin mutants is attributed to accelerated endocytosis via a syntaxin-4-associated pathway

Evesson, Frances J., Peat, Rachel A., Lek, Angela, Brilot, Fabienne, Lo, Harriet P., Dale, Russell C., Parton, Robert G., North, Kathryn N. and Cooper, Sandra T. (2010) Reduced plasma membrane expression of dysferlin mutants is attributed to accelerated endocytosis via a syntaxin-4-associated pathway. Journal of Biological Chemistry, 285 37: 28529-28539. doi:10.1074/jbc.M110.111120

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Author Evesson, Frances J.
Peat, Rachel A.
Lek, Angela
Brilot, Fabienne
Lo, Harriet P.
Dale, Russell C.
Parton, Robert G.
North, Kathryn N.
Cooper, Sandra T.
Title Reduced plasma membrane expression of dysferlin mutants is attributed to accelerated endocytosis via a syntaxin-4-associated pathway
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 1083-351X
Publication date 2010-09-10
Sub-type Article (original research)
DOI 10.1074/jbc.M110.111120
Open Access Status File (Publisher version)
Volume 285
Issue 37
Start page 28529
End page 28539
Total pages 11
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Collection year 2011
Language eng
Subject C1
0601 Biochemistry and Cell Biology
0904 Chemical Engineering
Abstract Ferlins are an ancient family of C2 domain-containing proteins, with emerging roles in vesicular trafficking and human disease. Dysferlin mutations cause inherited muscular dystrophy, and dysferlin also shows abnormal plasma membrane expression in other forms of muscular dystrophy. We establish dysferlin as a short-lived (protein half-life ∼4–6 h) and transitory transmembrane protein (plasma membrane half-life ∼3 h), with a propensity for rapid endocytosis when mutated, and an association with a syntaxin-4 endocytic route. Dysferlin plasma membrane expression and endocytic rate is regulated by the C2B-FerI-C2C motif, with a critical role identified for C2C. Disruption of C2C dramatically reduces plasma membrane dysferlin (by 2.5-fold), due largely to accelerated endocytosis (by 2.5-fold). These properties of reduced efficiency of plasma membrane expression due to accelerated endocytosis are also a feature of patient missense mutant L344P (within FerI, adjacent to C2C). Importantly, dysferlin mutants that demonstrate accelerated endocytosis also display increased protein lability via endosomal proteolysis, implicating endosomal-mediated proteolytic degradation as a novel basis for dysferlin-deficiency in patients with single missense mutations. Vesicular labeling studies establish that dysferlin mutants rapidly transit from EEA1-positive early endosomes through to dextran-positive lysosomes, co-labeled by syntaxin-4 at multiple stages of endosomal transit. In summary, our studies define a transient biology for dysferlin, relevant to emerging patient therapeutics targeting dysferlin replacement. We introduce accelerated endosomal-directed degradation as a basis for lability of dysferlin missense mutants in dysferlinopathy, and show that dysferlin and syntaxin-4 similarly transit a common endosomal pathway in skeletal muscle cells. Copyright © 2011 by American Society for Biochemistry and Molecular Biology
Keyword Girdle Muscular-dystrophy
Fer-1-like Protein
3t3-l1 Adipocytes
Syntaxin 4
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
Institute for Molecular Bioscience - Publications
Centre for Microscopy and Microanalysis Publications
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Citation counts: TR Web of Science Citation Count  Cited 22 times in Thomson Reuters Web of Science Article | Citations
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Created: Sun, 26 Sep 2010, 00:04:23 EST